ABSTRACT We propose to perform a population-based genetic epidemiological study of cocaine use disorder (CUD) in the region of Rio Grande Brazil to characterize the role of environmental stressors, both trauma exposure and HIV infection, on epigenetic signatures and gene-environment interactions in patients with CUD. Using already available DNA from 1000 CUD subjects and 1000 controls we will examine genome- wide associations and gene environment interactions (Aim 1), the relationship between traumatic stress and DNA methylation (Aim 2), and the additive effect of HIV infection as a biological stressor on DNA methylation (Aim 3). All molecular assessments will be correlated with behavioral and physiologic evaluations which are available from all individuals, to identify potential risk markers for CUD. These studies will examine the following hypotheses: 1) Genes involved in stress regulation will be associated with CUD, and CUD severity 2) Exposure to life stress and adversity (i.e., trauma) in genetically susceptible individuals represents a risk factor for development of CUD, and 3) HIV infection will have an additive effect on epigenetic modifications in genes related to stress regulation in subjects with CUD. The PI?s of this application have an established collaboration and history of research capacity building. The COllaborative Case-Control INitiativE in crack addiction (COCCaINE) project was initiated in 2014 as the result of needs assessment discussions between Drs. Grassi-Oliveira and Walss-Bass. This project forms the basis for the current application to the Fogarty International Center. As part of this application we will enhance research capacity and infrastructure (Aim 4) by implementing training programs in molecular epidemiology, bioinformatics, and management of substance use disorders and trauma for investigators in the area of Rio Grande Brazil. During the first year we will organize week-long theoretical and practical workshops taught by experts from UTHealth in Houston. During the second, third, fourth, and fifth years of the award we propose to create mini-fellowship programs for Brazilian investigators to travel to the United States for training. These training activities will be of great value for the research capacity building and development of qualified human resources in Brazil, and for successful implementation of the research goals. The proposed studies will lead to a better understanding of how changes in DNA methylation, as modulated by genetic make-up and in combination with exposure to environmental insults, impacts CUD severity and may serve as a biomarker for development of more tailored and targeted treatments for this chronic and global public health problem.